An embolus is an intravascular solid, liquid or gaseous mass that travels through the bloodstream to a site spaced apart from its origin. The majority of all solid emboli are derived from venous and arterial thrombi. Indeed, thrombosis and embolism are so closely interrelated they give rise to the term thromboembolism.
Infarcts are areas of ischemic necrosis of tissue. They are usually caused by thromboembolic occlusion of a vessel. Thromboembolic infarctions of the heart, lungs and brain collectively are believed to account for more deaths than all forms of cancer and infectious disease combined. Thromboembolism and infarction is further believed to constitute the dominating clinical problems today in all industrialized nations.
A variety of reactive oxygen species (ROS) have been shown to inhibit or inactivate thrombin and other serine proteases. Photodynamic dyes in biological systems can generate the ROS which specifically targets the vascular endothelium mimicking naturally occurring redox reactions. This results in targeted stimulation of the fibrinolytic system (i.e., lysis of existing thrombi). The inactivation of specific blood clotting factors along with the resultant physiologic response to the specifically targeted ROS, leads to an overall systemic anticoagulation state which prevents future thrombus formation.
Present anticoagulant therapies used for inhibition of thrombi formation such as heparins and coumarins, have a number of untoward and sometimes unexpected effects. Discovery of the human Thrombin-activatable fibrinolysis inhibitor (TAFI) anifibrinolytic system has provided strong evidence that while the use of these anticoagulants may effectively prevent the formation of future thrombi, they can paradoxically discourage fibrinolysis of existing thrombi. The result is a net addition of fibrin to existing thrombi. Similarly, tissue plasminogen activator (tPA) used to lyse existing thrombi is fraught with life threatening side effects. This therapy also has a narrow therapeutic window—less than three hours following thrombus formation. There is, thus, a need for new formulations having anticoagulant activity which does not favor growth of existing thrombi and is safer and more therapeutically flexible.
An illustrative embodiment of the present disclosure provides a preparation for treating arterial and venous thrombi. This preparation comprises a non-metal containing photodynamic dye and a fat soluble vitamin. In a further illustrative embodiment, the vitamin is vitamin K, despite being known for assisting blood clotting.
Indeed, it is known in the art that certain proteins that participate in the blood clotting cascade are vitamin K dependent. Obviously this is a double-edged sword. In the context of wound clotting, vitamin K can be beneficial. In the context of pathologic blood clotting or thrombus formation within an artery or vein, however, vitamin K can be problematic. It is therefore, believed, that vitamin K would not be an obvious choice in the field of anticoagulant pharmaceuticals
In medicine, vitamin K is used to promote the clotting of blood. In human physiology, vitamin K is essential in order for the blood clotting cascade to function properly and therefore for blood to have the capability of clotting. The subject matter of the present disclosure employs vitamin K to create the opposite effect. When the formulation of the current invention is compounded in the particular order, the hydrocarbon side chain of vitamin K is cleaved from the mother quinone base of the vitamin K derivative.
This is believed accomplished by mixing vitamin K with Geraniol Tetroxane. When this combination is then mixed with verteporfin, it is believed that the operative porphyrin-quinone complex is generated. It is this complex that is able to produce the necessary reactive oxygen species at specifically targeted sites in a ‘cyclic manner’ which produces said effects, not the vitamin K. If the formulation is not mixed in the proper order, it is believed that vitamin K will maintain its original structure and be available to make its usual contribution as the major promoter of blood clotting. In any event, adding vitamin K in any way shape or form to a compound designed to prevent blood clotting or designed to destroy existing blood clots would be counter-intuitive.
In the above and alternative embodiments, the preparation may also include: a photodynamic dye selected from a group consisting of a tricarbocyanine dye, tetramethylthionine chloride dye, a xanthene dye, and a benzo-porphyrin derivative (BPD) such as verteporfin, one of the fat soluble vitamins being vitamin A, D, E and K; the fat soluble vitamin being vitamin K; the photodynamic dyes being selected from a group consisting of methylene blue, indocyanine green, rose bengal, and verteporfin; verteporfin being combined together with the fat soluble vitamin; this combination being combined with a sodium salt; the sodium salt being sodium iodide; this combination being mixed into a physiologic carrier solution containing a metallic additive selected from the group consisting of gold, silver, copper, manganese and magnesium; and a readily available electron donor compatible with mammalian blood.
Another illustrative embodiment of the present disclosure provides a preparation for treating and preventing arterial and venous thrombi. This preparation's formulation comprises a fat soluble vitamin combined with a first solvent; this combination is then diluted with a second solvent; a first non-metal containing photodynamic dye is then chemically attached to the functional quinone group of the fat soluble vitamin in this mixture; one to three other non-metal containing photodynamic dyes are added to this mixture; a sodium salt is added to this mixture; and finally a second portion of the first solvent is added to this mixture.
In the above and alternative embodiments, the preparation may also include: the fat soluble vitamin being about 0.01 wt % vitamin K; the first solvent being about 20 wt % geraniol tetroxane in DMSO; the second solvent being about 99% DMSO; the first non-metal containing photodynamic dye is about 0.01 wt % verteporfin; and the second non-metal containing photodynamic dye is about 0.0088 wt % methylene blue; (sodium iodide solution can be substituted for IC Green) a third non-metal containing photodynamic dye being about 0.0574 wt % rose bengal; the first solvent comprising dimethyl sulfoxide and carboxylic acid derivatives; the second solvent comprising dimethyl sulfoxide; the second non-metal containing photodynamic dye being selected from a group consisting of verteporfin, indocyanine green, methylene blue and rose bengal; and a sodium solution or sodium salt, such as sodium iodide in a liquid form combined with the first portion of the second solvent combined with the first non-metal containing photodynamic dye, fat soluble vitamin, and first solvent combined with the second portion of the second solvent combined with the second non-metal containing photodynamic dye.
Yet another illustrative embodiment of the present disclosure provides a method of administration for treatment and prophylaxis of arterial and venous thrombi. This illustrative method comprises the steps of: combining a non-metal containing photodynamic dye and a fat soluble vitamin; combining the non-metal containing photodynamic dye and fat soluble vitamin with a sodium solution, such as about 0.9% sodium chloride (NaCl) and administering the combination of non-metal containing photodynamic dye, fat soluble vitamin, and sodium solution as an intravenous drip.
In the above and alternative embodiments, the method may also include one or more of the following steps: administering the intravenous drip for about 10 to 60 minutes; repeating the administration of the intravenous drip on a daily basis as needed for up to about eight days; combining a non-metal containing photodynamic dye that is selected from a group consisting of a tricarbocyanine dye, tetramethylthionine chloride dye, a xanthene dye and a benzo-porphyrin derivative dye; combining the fat soluble vitamin that is selected from a group consisting of vitamin A, vitamin D, vitamin E and vitamin K; combining the photodynamic dye that is selected from a group consisting of verteporfin, methylene blue, indocyanine green and rose bengal; combining the non-metal containing photodynamic dye and fat soluble vitamin with a sodium salt solution, such as sodium iodide; combining the non-metal containing photodynamic dye, fat soluble vitamin and salt solution such as with a sodium chloride metallic additive; and combining the non-metal containing photodynamic dye, fat soluble vitamin and salt solution with the metallic additive that is selected from a group consisting of gold, silver, copper, manganese and magnesium; vitamin K being added to a first solvent—Geraniol Tetroxane in DMSO, this being added to a second solvent—99% DMSO, this being added to verteporfin, this being diluted into more of the second solvent, sodium iodide being added, Methylene Blue being added, rose bengal being added, this being added to a physiologic carrier solution such as about 0.9% Sodium Chloride containing a metallic additive that is selected from the group consisting of gold, silver, copper, manganese and magnesium and an electron donor that is compatible with mammalian blood such as Vitamin C.
Further embodiments of the present disclosure provide compounds containing regioisomers of one or more of the following in combination with a fat-soluble vitamin, a non-metal containing benzoporphyrin derivative (BPD) photodynamic dye, and/or a synthetic tricarbocyanine photodynamic dye, and/or a tetramethylthionine chloride dye, and/or a xanthene dye for the treatment and prevention of thrombi and thrombus formation and other vascular related disease processes.
Still further embodiments of the present disclosure provide compounds containing regioisomers of one or more of the following in combination with a synthetic fat-soluble vitamin, a synthetic non-metal containing BPD photodynamic dye, a synthetic tricarbocyanine photodynamic dye, a synthetic tetramethylthionine chloride dye, or a xanthene dye for treatment and prevention of thrombi and thrombus formation and other vascular related disease processes.
Additional features and advantages of the formulation, preparation, and administration of the compound will become apparent to those skilled in the art upon consideration of the following detailed descriptions exemplifying the best mode of carrying out the formulation, preparation, and administration of the compound as presently perceived.